Drugs affecting hemostasis

DR. HUSSAIN ADDAI

ALJABERY
M.B.CH.B. M.SC. ( PHARMA.)
D.M.R.D. F.I.B.M.C ( RADIOLOGY)
Basic information

 Hemostasis is the spontaneous arrest of bleeding from damaged blood

vessel.
▌The coagulation system:
 It consists of a number of plasm proteins(factors). Each factor
 activates another till activation of fibrinogen to forfibrin.
 Activation cascade is done through systems: the intrinsic system (can be
monitored by the activated partialthromboplastin tissue “APTT )and the
extrinsic system (can be monitor by prothrombin time).
Prevention of clotting:

§ Plasma contains a number of proteins that normally prevent clotting

through inhibition of clotting factors(e.g. antithrombin III).
§ Heparin activates antithrombin III thus inhibits activation of factors IX, X, XI,
and XII.
§ Oral anticoagulants inhibit synthesis of clotting factors by the liver.
Dissolution of blood clots:

§ There are other plasma proteins that can dissolve blood clots (i.e.
fibrinolytic system e.g. plasmin).
§ There are some drugs hat activate plasminogen to form the active plasmin
and thus enhance fibrinolysis (e.g. streptokinase, urokinase, etc.).
§ Aminocaproic acid is n inhibitor of fibrinolysis.
█ DRUGS THAT PREVENT COAGULATION (ANTICOAGULANT )
Heparin-Induced Skin Necrosis
Low-molecular -weight heparins (LMWH) (Enoxparin –
Dalteparin)

§ Standard (unfractionated) heparin is a mixture of different

molecular
weight fractions (MW 3000-30,000 Da) that can affect more than one
coagulation factor and produce thrombocytopenia (↑ risk of bleeding).
§ LMWH has a MW less than 8000 Da that makes it specific for factor X with
minimal effects on platelets and other clotting factors.
 Direct thrombin inhibitors (DTIs)

 Bivalirudin
- It is a synthetic hirudin analogue (hirudin is a direct thrombin inhibitor peptide present in the saliva of
medicinal leech).
- Bivalirudin is a reversible and short-acting DTI. It is given
i.v.
- It is approved as alternative to heparin to treat patients with heparin-induced thrombocytopenia.
- Bleeding is the major side effect.
 Argatroban - Synthetic compound that binds reversibly to thrombin.
- It can be used as alternative to heparin to treat patients with heparin-induced thrombocytopenia.
- It is given i.v. and has immediate onset of action.
 Dabigatran
- It is the first oral DTI approved by the FDA in 2010.
- It was found superior to warfarin in preventing the risk of stroke and systemic embolism in susceptible
patients.
 Use of anticoagulants during pregnancy

– Pregnancy is a hypercoagulable state due to increase levels of coagulation factors

and venous stasis. Pegnancy increases the risk of venous thrombosis and pulmonary
embolism.
– The use of warfarin in the first trimester is associated with birth defects (5%), while its u
near fullterm increases the risk of fetal hemorrhage.
– Neither UFH nor LMWH cross the placenta; therefore, do not cause fetal bleeding or
teratogenicity, but they can reduce bone mass density and cause osteoporosis if used
throught pregnancy.
– Anticoagulation is recommended in most pregnant patients with a mechanical heart
valve. The American College of Chest Physicians (ACCP) recommends the use LMWH
until 13 weeks' gestation, THEN change to warfarin until the patient is close to delivery (3
weeks), and THEN restart LMWH. Long-term anticoagulants should be resumed
postpartum.
 Contraindications of anticoagulant therapy

Hematological: – Hemorrhagic blood diseases e.g. hemophilia & thrombocytopenia.

Neurological: – Recent hemorrhagic stroke within 3 weeks.
– Recent brain or eye surgery.
CVS: – Subacute bacterial endocarditis (SBE).
– Uncontrolled hypertension (→ risk of cerebral bleeding).
GIT: – Active PU, esophageal varices, and hemorrhagic pancreatitis
– Active inflammatory bowel disease (ulcerative colitis).
Liver: – Liver failure (this patient has bleeding tendency)
Renal: – Renal failure.
Gynecological: – Threatened abortion.
– Warfarin is not given in the first trimester.
Drug interactions of oral anticoagulants (warfarin)
█ FIBRINOLYTIC (THROMBOLYTIC) DRUG

§ Normally, when a fibrin clot is formed, plasminogen gets in contact with his clot and
become activate into plasmin by the help of naturally occurring tissue plasminogen
activators (t-PAs). Plasmin causes lysis of the clot.
§ These endogenous activators preferentially activate plasminogen that is bound to fibrin,
which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic
activation.
§ Fibrinolytic drugs cause rapid activation f plasminogen to form plasmin, but unfortunately,
they may activate both fibrin-bound plasminogen and circulating plasminogen thus, both
protective hemostatic thrombi and pathogenic thromboembolic are broken down (→ risk
of bleeding).
Streptokinase

§ Streptokinase is a protein (not an enzyme) that is isolated from streptococci; it

activates plasminogen into plasmin non-enzymatically.
§ It may be antigenic (causes allergy) in some people.
Urokinase

§ Urokinase is a protease originally isolated from urine; the drug is now

prepared in recombinant for from cultured kidney cells.
§ It is less antigenic than streptokinase.
Recombinant issue plasminogen activators (t- PAs): (Alteplase,
reteplase, and tenecteplase)

§ They are recombinant human proteins produced in cultured cells.

§ They are most specific to fibrin-bound plasminogen local activation of
plasmin at the thrombus site reduces the incidence of systemic bleeding.
§ Reteplase and tenecteplase have long half-life. The long half-life
permits admministratio as a bolus i.v. injection rather than by continues
infusion. (two injections i.v. separated by 30 minutes for reteplase one single
i.v. injection for tenecteplase).
Therapeutic uses of thrombolytic drugs

§ They are given by i.v.route in cases of acute myocardial infarction, ischemic stroke,
pulmonary embolism, and arterial thrombosis.
§ In cases of acute MI, they should be given within 12 h of onset. The maximum benefit is
obtained if treatment is given within 90 minutes of the onset of pain.
§ Before thrombolysis, care should be taken to ensure there is no liability for bleeding in a
critical site e.g. retina, CNS, etc.
Adverse effects of thrombolytic drugs

– Systemic bleeding is the major adverse effect–. The risk is high with streptokinase
and low with the recent recombinant tissue plasminogen activators.
- Streptokinase can cause allergy fever, and hypotension during i.v. infusion.
█ antiplatelet (antithrombotic) drugs

Aspirin
§ Aspirin inhibit platelet aggregation by:
– Irreversible inhibition of C X enzyme → ↓ TXA2 → ↓ platelet aggregation. Irreversible
–
acetylation of platelet cell membranes → ↓ platelet adhesions. –Decrease platelet ADP
synthesis → decrease platelet accumulation.
§ At higher doses (> 325 mg/day), aspirin may decrease endothelial synthesis of PGI2, which
inhibits platelet activity. Low doses (75-150 mg/day) ↓ synthesis of platelet TXA2 more than
PGI2 in endothelial cells and avoid this effect.
§ Other NSAID do not have comparable antithrombotic activity.
Blockers of platelet ADP receptors:
(Ticlopedine, clopidogrel, prasugrel)

§ These drugs irreversibly inhibit the binding of ADP to its receptor on platelets and,
thereby, inhibit the activation of the glycoprotein IIb/IIIa receptors required for platelets to
bind to fibrinogen and to each other.
Clopidogrels approved for prophylaxis of thrombosis in both cerebrovascular and cardiovascular
disease (e.g. coronary artery disease, coronary angioplasty, peripheral vascular disease, etc.).
The maintenance dose is 75 g/d orally.
§ Clopidogrel is a prodrug, and its therapeutic efficacy relies entirely on its active metabolite.
Some people have genetic deficiency in t e enzymes that metabolize clopidogrel; they are call d
“poor metabolizers”, and cannot benefit from this drug.
§ Ticlopedine has been largely replaced by clopidogrel be cause of serious adverse effects
(neutropenia and bleeding . Clopidogrelhas fewer incidence of these effects.
Blockers of platelet glycoprotein IIb/IIIa receptors:
(Abciximab, eptifibatide, tirofiban)

§ Activation of this receptor complex is the “final common pathway” for platelet aggregation
and binding with fibrinogen. persons lacking this receptor have bleeding disorder called
Glanzmann’s thrombasthenia.
§ Abciximab is the Fab fragment of a monoclonal antibody that binds to gpIIb/IIIa and blocks
binding of platelets to fibrinogen.
§ Eptifibatide is a small synthetic peptide that competitively blocks gpIIb/IIIa receptor.
§ Tirofiban is a peptide of low MW that binds to the gpIb/IIIa receptor.
§ These drugs have bee approved for use in patient undergoing percutaneous coronary
intervention, for unstable angina, and for post-MI.
§ Dipyridamole

§ Dipyridamole inhibits phosphodiesterase (PDE) enzyme → ↑ cGMP → VD and

inhibition of platelet activity. It also inhibit uptake of adenosine into platelets and
RBCs leading to extracellular accumulation and prolongation of its action.
§ The use of dipyridamole as an antithrombotic agent is limited to prophylaxis
(combined with warfarin) in patients with prosthetic ( mechanical) heart valves.